Vasospasm is a constriction of blood vessels, resulting in ischemia of the tissue supplied by the blood vessels. Prolonged spasm in arteries, veins, and vein grafts has been described as a physiologic complication in microsurgery for over 20 years (Buncke, H. J, Microsurgery: Transplantation-Replantation, on-line edition, Chapter 36). Vasospasm results from several processes including intrinsic smooth muscle contraction, local noradrenaline metabolism, neurogenic and hormonal processes, and prostaglandin metabolism. Topical agents, such as magnesium sulfate, lidocaine, papaverine and chlorpromazine have been reported to successfully relieve vasospasm. Other described methods for relieving vasospasm include nerve blocks, systemic adrenergic agents and systemic vasodilating agents such as sodium nitroprusside. Id at page 2. Experimental attempts to find roles for modifiers of prostaglandin function, sympatholytics, calcium channel blockers and numerous other drugs have generally not succeeded in producing either clearly applicable models or reproducibly positive results. Id at page 5. Vasospasm may be elicited by cold, mechanical trauma or chemical mediators, including adrenalin.
If circulation is not re-established in time, tissue damage may result due to reperfusion injury. Reperfusion injury refers to the cellular changes and tissue damage seen after a period of total ischemia followed by reperfusion. Extremity replantation, organ transplantation, free flap tissue reconstruction and even myocardial infarction and stroke are all clinical examples of interval tissue ischemia which can lead to tissue loss due to reperfusion injury after blood flow is re-established. Tissue reperfusion injury, seen in its full clinical extent as the no-reflow phenomenon, appears as inflammatory response to reperfusion, resulting in the ultimate death of the tissue.
Prostaglandin E1 is a derivative of prostanoic acid, a 20-carbon atom lipid acid, represented by the formula:
and is commercially available, e.g., from Chinoin Pharmaceutical and Chemical Works Ltd. (Budapest, Hungary) under the designation “Alprostadil USP,” from Pharmacia & Upjohn under the designation “Caverject”. Prostaglandin E1 complexed with alpha-cyclodextrin is available as alprostatil alfadex from Ono Pharmaceuticals (Japan) and in an injectable form under the designation “Edex®” or “Viradex®” from Schwarz Pharma (Germany).
Prostaglandin E1 is a vasodilator useful to maintain open blood vessels and, therefore, to treat peripheral vascular disease among other ailments. While the potential benefits from transdermal delivery of prostaglandin E1 have long been recognized, prior efforts at developing a topical composition for prostaglandin delivery have not been fully successful. Working alone, most drugs, prostaglandin formulations included, do not sufficiently permeate the skin to provide drug concentration levels comparable to those obtained from other drug delivery routes. To overcome this problem, topical drug formulations typically include a skin penetration enhancer. Skin penetration enhancers also may be referred to as absorption enhancers, accelerants, adjuvants, solubilizers, sorption promoters, etc. Whatever the name, such agents serve to improve drug absorption across the skin. Ideal penetration enhancers not only increase drug flux across the skin, but do so without irritating, sensitizing, or damaging skin. Furthermore, ideal penetration enhancers should not adversely affect the physical qualities of the available dosage forms (e.g., cream or gel), or the cosmetic quality of the topical composition.
A wide variety of compounds have been evaluated as to their effectiveness in enhancing the rate of penetration of drugs through the skin. See, for example, Percutaneous Penetration Enhancers, Maibach H. I. and Smith H. E. (eds.), CRC Press, Inc., Boca Raton, Fla. (1995), which surveys the use and testing of various skin penetration enhancers, and Büyüktimkin et al., Chemical Means of Transdermal Drug Permeation Enhancement in Transdermal and Topical Drug Delivery Systems, Gosh T. K., Pfister W. R., Yum S. I. (Eds.), Interpharm Press Inc., Buffalo Grove, Ill. (1997).